title: LOX-1, a bridge between GLP-1R and mitochondrial ROS generation in human vascular smooth muscle cells.
abstract: A growing body of evidence indicates that glucagon-like peptide-1 (GLP-1) agonists or dipeptidyl peptidase-4 (DPP-4) inhibitors play an important role in modulating oxidant stress in vascular beds. However, the underlying mechanism of this process remains unclear. In recent studies, we observed an increase in GLP-1 receptor (GLP-1R) expression in the aorta of LOX-1 knock-out mice. Since LOX-1 is a pivotal regulator of reactive oxygen species (ROS), we conducted studies to identify relationship between LOX-1, ROS and GLP-1 agonism or DPP-4 antagonism. We observed a sustained decrease in GLP-1R expression in human vascular smooth muscle cells (VSMCs) treated with ox-LDL. When VSMCs were treated with different concentration of liraglutide (a GLP-1 agonist) or NVPDPP728 (a DPP-4 inhibitor), expression of ROS decreased compared with ox-LDL alone treatment. To further prove that LOX-1 plays a pivotal role in ROS and GLP-1R expression, we treated VSMCs with LOX-1 antibody or transfected cells with human LOX-1 cDNA. The inhibitory effect of ox-LDL on GLP-1R expression was reversed with anti-LOX-1 antibody treatment, while the inhibitory effect of liraglutide and NVPDPP728 on ROS generation was attenuated when cells were transfected with LOX-1 cDNA. Our results suggest that LOX-1 may play a bridging role in GLP-1 activation and ROS interaction.
authors.affiliation: Department of Cardiology, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR 72212, United States.
authors.forename: Yao
authors.initials: Y
authors.lastname: Dai
authors.forename: Federico
authors.initials: F
authors.lastname: Mercanti
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Dai
authors.forename: Xianwei
authors.initials: X
authors.lastname: Wang
authors.forename: Zufeng
authors.initials: Z
authors.lastname: Ding
authors.forename: Naga Venkata
authors.initials: NV
authors.lastname: Pothineni
authors.forename: Jawahar L
authors.initials: JL
authors.lastname: Mehta
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D005453:Fluorescence; D017353:Gene Deletion; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology; D000069450:Liraglutide; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D018027:Receptors, Glucagon / Q000378:metabolism*; D051127:Scavenger Receptors, Class E / Q000378:metabolism*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D008077:Lipoproteins, LDL; C495137:OLR1 protein, human; C495138:Olr1 protein, mouse; D017382:Reactive Oxygen Species; D018027:Receptors, Glucagon; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1
keywords: GLP-1; LOX-1; Ox-LDL; ROS